The objective of this program is to improve the quantitative gastrointestinal absorption and central nervous system (CNS) absorption of thiamine via the pro-drug approach. A number of encephalopathies - including Wernicke's encephalopathy in alcoholics and the terminal child disease, Leigh's disease - have been shown or have been postulated to result from inhibited gastrointestinal or inhibited CNS absorption of thiamine. We have synthesized a series of neutral thiamine derivatives that will be passively absorbed from the gastrointestinal tract and the blood brain barrier and be capable of regenerating thiamine via normal biochemical pathways once absorbed into blood and brain tissue. The synthesized pro-drugs will be administered both orally and parenterally to rats, and regenerated thiamine levels in blood followed via the thiochrome method. Selected pro-drug-derivatives using C14 thiamine will be synthesized and the CNS absorption of the pro-drugs and the regenerated thiamine levels followed. An assay method has been devised to allow the analysis of both thiamine and intact thiamine pro-drug. The absorption rates of thiamine compared to its more lipophilic pro-drugs will be determined in rats using the in situ rat perfusion technique. Thiamine and its pro-drug will be analyzed from the perfusion solutions using high pressure liquid chromatography with correction for water flux using C14-PEG4000. An attempt will be made to correlate the improved absorption across the gastrointestinal tract and into the CNS of thiamine from its pro-drug-forms, using thiamine as a control to the in vivo regeneration rate and the physical properties of the pro-drugs.